FDA Doesnt Anticipate Safety Review in Developing Pre-DSHEA List

An FDA official has signaled her agency does not intend to conduct a safety review as part of an ambitious initiative to develop a list of “old" dietary ingredients marketed before Oct. 15, 1994.

Dietary ingredients marketed before the above date are exempt from a safety-related notification to FDA, per the 1994 Dietary Supplement Health and Education Act (DSHEA).

Advocacy groups and others want to protect consumers from dangerous ingredients—including those that may be “old"—in dietary supplements.

Commenting last week on efforts to develop an authoritative list of “old dietary ingredients" (ODIs), an FDA official, Cara Welch, Ph.D., said, “I don’t expect our review will be a safety review. That’s a bit more than we signed on for."

Added Steven Tave, director of FDA’s Office of Dietary Supplement Programs (ODSP), in an emailed statement: “An authoritative list of pre-DSHEA dietary ingredients will not be a list of safe ingredients. It would represent only a list of ingredients which were marketed in the United States before Oct. 15, 1994 and therefore do not require submission of an NDI [new dietary ingredient] notification." 

However, Welch—senior advisor to ODSP—noted manufacturers of dietary supplements have an obligation to ensure that their products are safe, and FDA has authority under DSHEA to take enforcement action against an adulterated product.

“We still have an adulteration provision tied to safety," she explained last week at the Rocky Mountain Dietary Supplement Forum in Boulder, Colorado, which was hosted by the FDA Compliance Group LLC.  

If a dietary supplement is entirely comprised of ODIs, “and it presents … a significant or unreasonable risk of illness or injury to consumers, we can charge that product as adulterated," Welch explained. “Can and will."

She recently highlighted a well-established ingredient sold in dietary supplements that was targeted by FDA: caffeine. In 2015, FDA issued warning letters to five distributors of powdered caffeine. The agency contended the dietary supplements were adulterated because they posed a “significant or unreasonable risk of illness or injury under the conditions of use recommended or suggested in the labeling."

Powdered caffeine has been linked to adverse health effects, including the death of a teenager who passed away just three days before his high school graduation.

“That is an unsafe product," Welch said during the supplement forum, describing powdered caffeine. “It’s really hard to use that product safely, and FDA has charged some of those products as adulterated…."

There are perhaps hundreds or thousands of supplement ingredients exempt from the NDI notification (NDIN) requirement. That’s because the dietary ingredients were either marketed before Oct. 15, 1994, or the ingredients meet a separate exemption in DSHEA related to their presence “in the food supply as an article used for food in a form in which the food has not been chemically altered."

Aside from the above food-related NDIN exemption, NDIs cannot be introduced into interstate commerce unless FDA receives a premarket notification establishing their safety.

“The legal definition of ‘new dietary ingredient’ does not entail a safety assessment, but the significance of being a new dietary ingredient under the statute has a direct nexus to safety: a dietary ingredient is potentially subject to the pre-market safety notification requirement only if it is new," Tave explained. “The NDI notification process is critical because it is FDA’s only opportunity to spot dangerous products before they become available to consumers. Therefore, even though safety is not a direct factor in the chronological question of marketing status, it should be in our minds as we figure out how to compile an authoritative list."

Consumer advocacy groups are concerned with the safety of dietary ingredients—both old and novel ingredients. Laura MacCleery, director of regulatory affairs for the Center for Science in the Public Interest (CSPI), which petitioned FDA in December 2014 to ban the retail distribution of pure, powdered or liquid caffeine as a dietary supplement, recently objected to the use of the term “safe harbor" in association with any ODI list.

“Even though the notion of safety is not specifically part of a ‘grandfather’ clause, it is the elephant in the room," she said Oct. 3 during a public meeting hosted by FDA. “It is always the consideration from the consumer advocacy perspective, and if the system wasn’t broken, if we had a system in which [there was] rapid response to dangerous substances—either under DSHEA’s provision for removal of imminent hazards to public health or under the reasonable safety standard in the form sold, then we wouldn’t be as worried about a system that provides a so-called safe harbor or grandfather list of pre-DSHEA ingredients."

MacCleery suggested FDA consider using its limited resources to remove the most adulterated or dangerous substances from the market rather than focusing on an authoritative ODI list.

“The risk here … is that FDA would spend time and energy on a list that’s used mainly for marketing purposes by the industry and incorrectly labeled as safe harbor," she said, “yet the agency will not have made in fact any determination about safety—just prior use—and consumers will be even more deeply confused than they are already about whether FDA examines the safety of supplements."

Stephanie Scarmo, Ph.D., of The Pew Charitable Trusts, also noted the safety issue during the FDA meeting.

She said it would be important for the listing process to consider any changes to identity from the pre-DSHEA form, as well as conditions of use. She added FDA should take a conservative approach to creating a pre-DSHEA list, and the agency should have discretion to remove ingredients from any such list due to concerns about safety or documentation.

Pieter Cohen, M.D., is an associate professor of medicine at Harvard Medicine School who has studied products marketed as dietary supplements but containing potentially harmful substances. He told INSIDER he agreed with FDA that the process of listing ODIs is not the proper venue for a safety review.

The Massachusetts physician nonetheless recommended FDA restrict its list of ODIs to ingredients “that are identical in all respects to those previously sold." Cohen said “both the original source as well as the manufacturing specifications" should correlate to the ingredients marketed before Oct. 15, 1994.

“We have a multitude of studies that have demonstrated that without this safeguard traditional ingredients can be manipulated such that they become identical to prescription drugs, such as with yohimbe and red yeast rice," Cohen explained in an emailed statement.

It remains to be seen how broadly or narrowly FDA will interpret what meets the definition of a dietary ingredient marketed before Oct. 15, 1994 in its quest to develop an authoritative ODI list. However, the agency wants to ensure the public doesn’t misinterpret any official list as an endorsement or indication that the ingredients on it are safe.

“FDA and industry both must be exceedingly careful to make sure that consumers and health care practitioners do not fall under the misimpression that the appearance of any ingredient on a pre-DSHEA list suggests the ingredient is safe," Tave, FDA’s dietary supplement chief, said. “If we compile an authoritative list, it would be our expectation that firms should not communicate the ‘pre-DSHEA’ status of an ingredient to consumers because of the risk of misleading them about a determination of safety."